PT - JOURNAL ARTICLE AU - Rosemina Merchant AU - Carole Galligan AU - Manjunatha Ankathatti Munegowda AU - L Bruce Pearce AU - Peter Lloyd AU - Paul Smith AU - Fahar Merchant AU - Minh D To TI - Fine-tuned long-acting interleukin-2 superkine potentiates durable immune responses in mice and non-human primate AID - 10.1136/jitc-2021-003155 DP - 2022 Jan 01 TA - Journal for ImmunoTherapy of Cancer PG - e003155 VI - 10 IP - 1 4099 - http://jitc.bmj.com/content/10/1/e003155.short 4100 - http://jitc.bmj.com/content/10/1/e003155.full SO - J Immunother Cancer2022 Jan 01; 10 AB - Background Recombinant human interleukin-2 (rhIL-2, aldesleukin) is Food and Drug Administration approved for the treatment of metastatic melanoma and renal cell carcinoma and has achieved durable response in a subset of patients. However, its utility as an immunotherapeutic drug is limited by undesirable activation of immune suppressive regulatory T cells (Tregs) and a short half-life requiring frequent high dose administration, leading to unacceptable toxicities. We have engineered MDNA11, a long-acting IL-2 superkine, to overcome these limitations by (1) modifying receptor selectivity in favor of anti-cancer immune cells to increase therapeutic efficacy and (2) fusion to human albumin to extend the pharmacokinetic (PK) profile, circumventing the need for frequent dosing.Methods MDNA11 was evaluated using in vitro and in vivo studies including: binding analyses to measure receptor affinity, IL-2 pathway signaling, PK studies in mice, and efficacy studies in syngeneic tumor models as single agent and in combination with immune checkpoint inhibitors. Finally, the safety and pharmacodynamic profile of MDNA11 was assessed in non-human primate (NHP).Results Binding studies with MDNA11 demonstrated increased affinity for IL-2Rβ (CD122) and no binding to IL-2Rα (CD25). As a result, MDNA11 exhibits reduced/limited Treg stimulation while triggering an enhanced activation of natural killer and naïve CD8 T cells compared with rhIL-2. When administered to animals with pre-established tumors, MDNA11 controlled tumor growth in a monotherapy setting and in combination with anti-PD1 or anti-CTLA4 to induce durable tumor clearance with a once weekly dosing regimen. In a NHP model, MDNA11 was well tolerated while triggering durable and potent immune responses including expansion of lymphocytes without significant effect on Tregs and eosinophils, the latter been linked to an increased risk of vascular leak syndrome.Conclusion MDNA11 is a next generation long-acting IL-2 immunotherapeutic with a highly favorable pharmacodynamic profile that translates to a strong therapeutic efficacy in preclinical tumor models and a strong and durable immune response in NHP.Data are available upon reasonable request. Data sets and material/reagents analyzed and/or used in this study are available upon reasonable request.